Cancer is increasingly common in canines. Canine cancers include solid tumors and lymphomas such as, e.g., cancers of the mammary glands, prostate, oropharynx, skin, gastrointestinal tract, lungs and bone. A number of canine cancers are highly aggressive.
Recently, studies have been directed toward elucidating the biological mechanism underlying canine cancers. Dysregulation of growth factor receptors (also known as receptor tyrosine kinases, RTKs) is a common mechanism by which normal cells can undergo malignant transformation. One particular RTK termed Met is over-expressed in 60-100% of human OSA, and is known to be aberrantly expressed in canine OSA (see, e.g., Ferracini et al., J Orthop Res 18, 253-6 (2000); Ferracini et al., Oncogene 10, 739-49 (1995); Ferracini et al., J Cell Physiol 184, 191-6 (2000); and Scotlandi et al., Am J Pathol 149, 1209-19 (1996)).
The proto-oncogene Met was originally identified as the transforming gene of a human OSA cell line (MNNG-HOS) (Cooper et al. Nature 311, 29-33 (1984)). The ligand for Met is hepatocyte growth factor (HGF, also known as scatter factor) (Nakamura, Prog Growth Factor Res 3, 67-85 (1991); Nakamura et al., Nature 342, 440-3 (1989); Shimomura et al., J Biol Chem 268, 22927-32 (1993)). Met-HGF interactions promote an array of cellular responses such as proliferation, scattering (motility), and branching morphogenesis (Kan et al., Biochem Biophys Res Commun 174, 331-7 (1991); Montesano et al., Cell 67, 901-8 (1991); Weidner et al., J Cell Biol 111, 2097-108 (1990); Grant et al., PNAS USA 90, 1937-41 (1993); Birchmeier and Gherardi, Trends Cell Biol 8, 404-10 (1998)). Binding of HGF to Met initiates receptor dimerization and autophosphorylation at multiple tyrosine residues, resulting in a cascade of downstream signaling events including phosphorylation of adaptor proteins (Gab-1, Grb2, Shc, c-Cb1) and activation of PI3K, ERK1/2, FAK and PLCγ (Jiang et al., Crit Rev Oncol Hematol 29, 209-48 (1999); Maulik et al., Cytokine Growth Factor Rev 13, 41-59 (2002)). These signals are important in mediating a wide range of biological activities, including embryological development, wound healing, tissue regeneration, angiogenesis, invasion, and morphogenic differentiation (Jiang et al., Crit Rev Oncol Hematol 29, 209-48 (1999); Maulik et al., Cytokine Growth Factor Rev 13, 41-59 (2002); Birchmeier and Gherardi, Trends Cell Biol 8, 404-10 (1998)).
Increasing evidence suggests that both Met and HGF are dysregulated in a variety of canine, murine, and human cancers through mutation, overexpression, or co-expression of Met and HGF (Birchmeier et al., Nat Rev Mol Cell Biol 4, 915-25 (2003); Jeffers et al., Proc Natl Acad Sci USA 94, 11445-50 (1997); Jeffers et al., Mol Cell Biol 16, 1115-25 (1996); Jeffers et al., Oncogene 13, 853-6 (1996); Jeffers et al., PNAS USA 95, 14417-22 (1998); Pennacchietti et al., Cancer Cell 3, 347-61 (2003); Scarpino et al., J Pathol 202, 352-8 (2004); Schmidt et al., Cancer Res 58, 1719-22 (1998); Schmidt et al., Nat Genet 16, 68-73 (1997); Ma et al., Cancer Res 63, 6272-81 (2003); Lindor et al., Genet Test 5, 101-6 (2001); Lee et al., Oncogene 19, 4947-53 (2000); Di Renzo et al., Oncogene 19, 1547-55 (2000); Park et al., Cancer Res 59, 307-10 (1999); Ferracini et al., Oncogene 10, 739-49 (1995); Ferracini et al., J Cell Physiol 184, 191-6 (2000); Scotlandi et al., Am J Pathol 149, 1209-19 (1996); Tsao et al., Lung Cancer 20, 1-16 (1998); Ruco et al., J Pathol 180, 266-70 (1996); Ruco et al., J Pathol 194, 4-8 (2001)). It is also important to note that aberrant Met expression and/or function through mutation is associated with high tumor grade and a poor prognosis in a variety of human cancers (Di Renzo et al., Clin Cancer Res 1, 147-54 (1995); Baykal et al., Gynecol Oncol 88, 123-9 (2003); Carneiro, F. and Sobrinho-Simoes, M., Cancer 88, 238-40 (2000); Nakajima et al., Cancer 85, 1894-902 (1999); Takeuchi et al., Clin Cancer Res 9, 1480-8 (2003); Di Renzo et al., Oncogene 7, 2549-53 (1992)). Together, this data suggests that inappropriate expression or function of Met contributes to both tumor development and tumor progression.
Met dysregulation has also been implicated in canine cancer, specifically osteosarcoma (OSA). OSA is the most common bone tumor in dogs, representing approximately 85% of all bone tumors (Withrow et al., Clin Orthop, 159-68 (1991); Withrow and MacEwen, Small animal clinical oncology, xvii, 736 (W.B. Saunders, Philadelphia, 2001)). Both large and giant breed dogs are at a higher risk for the development of OSA, with certain breeds such as Rotweillers and Irish Wolfhounds over-represented (Withrow et al., Clin Orthop, 159-68 (1991); Withrow and MacEwen, 2001, supra).
OSA is a very aggressive tumor, causing lysis of the affected bone leading to a progressive lameness. While less than 10% of dogs have radiographically detectable pulmonary metastases at the time of presentation, over 90% have microscopic metastatic disease. Treatment involves removal of the primary tumor through either limb amputation or limb spare surgery. Amputation alone leads to a median survival time of 3-4 months, with nearly all dogs succumbing to metastasis within 1 year (Withrow et al., Clin Orthop, 159-68 (1991); Withrow. and MacEwen, 2001, supra). Survival times are extended to 8-12 months if adjuvant chemotherapy with cisplatin, adriamycin, or carboplatin is used (reviewed in (Withrow and MacEwen, 2001, supra); Chun and de Lorimier, Vet Clin North Am Small Anim Pract 33, 491-516, vi (2003))). However, less than 20% of patients will survive longer than 2 years. Recent efforts at co-administering adriamycin and a platinum compound have not improved survival times (Chun and de Lorimier, 2003, supra). In one report, 5 of 7 canine osteosarcoma (OSA) tumor samples exhibited high levels of Met expression as assessed by Northern analysis (Ferracini et al., J Orthop Res 18, 253-6 (2000)). In addition, a lung metastasis from one dog expressed Met at a higher level than the primary tumor. These results are similar to findings in human OSA in which 60%-95% of primary tumors and 80-100% of recurrences (local and distant) exhibit excessive Met expression (Ferracini et al., Oncogene 10, 739-49 (1995); Ferracini et al., J Cell Physiol 184, 191-6 (2000); Scotlandi et al., Am J Pathol 149, 1209-19 (1996)). Furthermore, Met was found to be overexpressed in multiple human OSA cell lines, and HGF stimulation induced phosphorylation, scattering and proliferation of these cells, although this effect varied in degree among the cell lines tested (Coltella et al., Faseb J 17, 1162-4 (2003)). Lastly, three canine OSA cell lines were recently demonstrated to express Met and to respond to HGF stimulation leading to Met phosphorylation (MacEwen et al., Clin Exp Metastasis 20, 421-30 (2003)).
Clearly, novel therapeutic approaches for the treatment of canine cancer are needed if significant improvements in clinical outcome are to occur.
It is therefore clear that there is a need in the art for more effective therapeutic and diagnostic approaches for treating and preventing canine cancers. The present invention addresses these and other needs.